The goal of this exploratory proposal is to study the role of TGFR3, also known as betaglycan, in T-cell development and immune responses. Although TGFR3 is broadly expressed in cells of both the innate and adaptive immune system, very little is known about its function in immunity. Loss of expression of TGFR3 in several cancers is associated with poor prognosis. We have recently reported that TGFR3 expression in thymocytes is developmentally regulated, and interruption of its signaling leads to inhibition o T-cell maturation. TGFR3-null mice exhibit embryonic lethality which has hampered studies to determine its function in the immune system. We have developed a novel conditional TGFR3fl/fl mouse that offers the opportunity to selectively target the inactivation of TGFR3 in tissues of choice. We show that induced inactivation of TGFR3 in the adult mouse leads to profound changes in T cell development. In mature T cells, inactivation of TGFR3 enhanced Th1 differentiation but diminished Th17 differentiation. These results reveal an indispensable function for TGFR3 in T cell development and differentiation. TGFR3 is a coreceptor and enhances the binding of TGF- family of molecules to TGFR1/TGFR2 heterodimer leading initiation of intracellular signals. TGFR3 also binds to inhibins with high affinity to antognize activin-dependent signaling. In addition to TGFR1/TGFR2 associated activity, TGFR3 can also independently modulate intracellular signals associated with activation and migration. For this proposal, the specific aims are: (1) to determine the role of TGFR3 in T cell development and selection; (2) to determine the role of TGFR3 in modulating the differentiation of nave T cells to effector cells and autoimmunity. Our proposed studies will move the field forward in our understanding of the biological properties of TGF- family of proteins with opportunities to develop new strategies for promoting immunity and/or targeting autoimmunity.